Cancer immunotherapy: immune checkpoint T cell/dendritic cell interactions Maintenance of T cell activation by stimulatory (eg TCR and OX40) and T cell/tumor cell interactions Neoantigens released by cancer cells in the tumor inhibitory regulators (eg CTLA4 and PD-1) fine-tune the immune response Tumor cells and non-transformed cells within the tumor microenvironment are processed by DCs and presented microenvironment will exploit the immune checkpoint on their cell surface. These antigen presenting cells (APCs) to prevent autoimmune inflammation or immune deficiency. In cancer, pathway inhibiting the anti-tumor immune response. are recognized by T cells, resulting in T cell priming and This leads to cancer progression. They achieve this by activation. DCs may also exhibit inhibitory receptors the balance between these inputs is tipped toward immunosuppression over-expressing inhibitory immune checkpoint molecules which act to balance the immune response, preventing leading to cancer progression. such as PD-L1 on their cell surface. These bind to inhibitory autoimmune inflammation. receptors on the T cell surface causing the immune cells T cell activation by a dendritic cell to deactivate. T cell activation by a dendritic cell T cell inhibition by tumor cell T cell inhibition by tumor cell OX40 OX40L TIM 3 Galectin 9 Naive T cell ICOS ICOSL TCR MHC I CD28 CD80 LAG 3 TCR MHC I T cell activation MHC II PD1 Activated T cell Dendritic cell T cell proliferation PDL1 Inhibited T cell Tumor cell T cell inhibition by a dendritic cell T cell inhibition by a dendritic cell T cell priming Activated T cell Immunotherapy Inhibitors which target negative regulators of immune cell CTLA4 CD86 Cancer immunity cycle function such as CTLA4, PD-L1, and CXCR4 have great potential for use as immunotherapies. Blocking the T cell Dendritic cell inhibitory signal results in an active immune response MDSC cell leading to tumor cell death. Tumor T cell activation by immunotherapy Antigen capture infiltration PD1 PDL1 Inhibited T cell Dendritic cell Antigens Tumor cell Regulators of T cell activation Mast cell Antigen Presenting Cell T Cell T Cell Regulation PD-L1 PD-1 Inhibition PD-L2 PD-1 n/a Tumor T cell Tumor apoptosis PDL1 CD80 / CD86 CD28 Activation Activated T cell PD1 CD80 / CD86 CTLA4 Inhibition Macrophage CTL Anti-PD-1 PD-1 inhibitors ICOSL ICOS Activation CD276 n/a Inhibition Anti-CTLA4 CXCR4 CTLA4 inhibitors B7-H4 n/a Inhibition CTLA4 ® B7-H5 CD28H Activation RabMAb Knockout-validated immuno-oncology antibodies CD86 n/a VISTA Inhibition PD-L1 [28-8] CXCR4 inhibitors - Highly specific orf human PD-L1; no cross-reactivity with human PD-L2 HVEM BTLA Inhibition - Generated using the extracellular domain of PD-L1 protein – observed membrane specific staining CD40 CD40L Activation Dendritic cell OX40L OX40 Activation CXCR4 [UMB2] PD-L1 [28-8] CXCR4 [UMB2] - Specific IHC/ICC signal in several cells and tissues including human CD137L CD137 Activation cervical carcinoma, Jurkat cells, and mouse embryonic tissues. CD70 CD27 Activation Key features - Available as Azide-free variants GAL9 TIM3 Inhibition - Knockout (KO) cell line validated in key applications: IHC, FC, WB - Available as Alexa Fluor® conjugated primary antibodies GITRL GITR Activation B-CAP Cells – high HCC70 Cells – medium ES-2 Cells – low COLO205 Cells – none (Cancer cell lines with varying levels of PD-L1 expression) MHC-II LAG-3 Inhibition www.abcam.com/cancer Copyright © 2018 Abcam, All rights reserved. RabMAb® is a registered trademark of Abcam. *Adapted from Pardoll, et al., 2012.